tbuckley/cabot-search huggingface dataset:
KS05.6.A Oral DNA vaccination targeting VEGFR2 combined with the anti-PD-L1 antibody avelumab in patients with progressive glioblastoma - final results. NCT03750071
Authors: W Wick, A Wick, O Chinot, F Sahm, A von Deimling, C Jungk, M Mansour, L Podola, H Lubenau, M Platten
Journal: Neuro-Oncology (2022)

Abstract Background Vascular endothelial growth factor receptor (VEGFR)2 overexpression on glioblastoma endothelia serves as a target for VEGFR2 primed T cells using VXM01 DNA vaccine encoding for VEGFR2. VXM01 is delivered in a bacterial Ty21a carrier suitable for oral administration. A previous phase I/II study in 14 patients with progressive glioblastoma showed a positive correlation of of VEGFR2 specific T cells as well as altered intra-tumoral immunity with prolonged overall survival. One partial response was reported with VXM01 alone. The current trial aimed at intensifying the efficacy signal and testing the co-administration of a checkpoint inhibitor. Material and Methods A multicentre, open-label phase I/II study (EudraCT 2017 003076 31) included 28 patients (25 non-resectable, 3 resectable) with progressive glioblastoma after standard chemoradiotherapy. VXM01 was administered on day 1, 3, 5, 7 followed by boostings q4w. Avelumab (800 mg) was given intravenously q2w. Treatment continued up to week 96 followed by a 2-year observation period. Endpoints included safety and tolerability, objective response rate (ORR), clinical response using immune-response assessment in Neurooncology criteria (iRANO), and immunological assays like ELISpot, FACS, and tumor immune biomarkers. Results Treatment with VXM01 106 or 107 CFU plus avelumab was completed in all patients. No treatment-related toxicities were observed. Three partial responses (according to iRANO) with tumor reductions of 58, 81 and 95% to baseline, respectively, were reported in the non-resectable patients (Objective response rate (ORR) was 12% (3/25)). Two of these patients were progression-free &amp;gt; 12 months. Best response in 3 additional non-resectable patients was SD including one patient progression-free &amp;gt; 6 months. In one resected patient, tumor shrinkage of 30% each was observed after initial treatment before resection as well as subsequent to incomplete resection, associated with survival &amp;gt; 18 months, and accompanied by an increase of intratumoral CD8+ T-cells. Conclusion VXM01 in combination with avelumab was safe and produced detectable peripheral VEGFR-2-specific immune responses. Three non-resected patients had an objective response, three more patients experienced best response stable disease. For future studies a patient enrichment strategy based on immune biomarkers might be envisaged.
P17.10.B Identification of mechanisms involved in the recurrence of glioblastoma by transcriptomic, proteomic and spatial profiling analysis
Authors: M Ritz, T Shekarian, T Martins, S Hogan, P Schmassmann, B Burger, G Hutter
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma (GBM) is the most aggressive and common brain tumor. Despite multimodal therapy which consists of complete tumor removal, chemo- and radiation therapy in most patients, the tumor recurs, and the overall survival of only 14 months remains very poor. To identify tumor-induced immune evasion and treatment resistance mechanisms induced during GBM recurrence, we aimed at characterizing the immunological/molecular changes in patient-matched treatment-naïve and recurrent GBM samples. Material and Methods Proteins and total RNA were extracted from 16 patient-matched treatment-naïve (primary) and recurrent GBM fresh frozen tumor samples. The expression of genes involved in brain immune responses were compared using Nanostring panels encompassing Cancer and Neuroinflammation genes. Proteomic was conducted using 6 patient-matched primary and recurrent tumor samples. Immunostaining was performed on a tissue microarray containing matched primary and recurrent tumor samples to identify tumor cells and microglia in order to assess spatial transcriptome of these specific cell types in situ using GeoMX technology. Moreover, correlation analysis of differentially genes and proteins with time to relapse was performed. Results Genes significantly differentially expressed between primary and recurrent tumors revealed genes overexpressed in recurrent tumors belonging to “FCGR-mediated Phagocytosis” and “synapse pruning” pathways. Proteomic confirmed the synaptic signalling considering overexpressed proteins. Correlation studies with the time to relapse indicated that higher expression of FCG receptors, complement molecules and synaptic components correlate with shorter time to relapse, sharing similarities with neurodegenerative/cognitive disorders such as schizophrenia and Alzheimer disease. The source for these molecules is under evaluation with the spatial transcriptomic analysis. Conclusion Upregulation of specific proteins such as FCG receptors, complement and synaptic components may result in more favourable conditions for tumor regrowth and may therefore be identified as negative predictors patient outcome. Interfering with these molecules may represent novel therapeutic options after initial GBM surgery.
P18.01.A The applicability of established clinical and histopathological risk factors for tumor recurrence during long-term perioperative care in meningioma patients
Authors: S Lüthge, A Steinbicker, S Schipmann, E M S Streckert, K Hess, O Grauer, W Paulus, W Stummer, B Brokinkel, D C Spille
Journal: Neuro-Oncology (2022)

Abstract Background Risk factors for the prediction of late-onset tumor recurrence in meningioma patients are sparse but needed to estimate duration and control intervals during long-term follow-up in meningioma patients. In this study, we therefore analyzed the value of established risk factors for postoperative meningioma recurrence for the prediction of long-term prognosis in a large, single-center series. Material and methods Correlations of established clinical (age, sex, tumor location, extent of resection), radiological (postoperative tumor volume) and histopathological variables (WHO grade, brain invasion) with tumor relapse were analyzed separately after 3, 5, and 10 years following microsurgery for primary diagnosed intracranial meningioma between 1991 and 2021 in uni- and multivariate analyses. The prognostic value was compared to findings in the entire cohort. Results Within a median follow-up of 29 months (range: 0-307 months), recurrence was observed in 141 patients (12%) after a median PFS of 36 months. PFS among the entire cohort (n=1218) at 3, 5, 10 and 15 years postoperatively were 90%, 84%, 74% and 70%, respectively. Among all patients included, skull base location (HR: 1.51, 95%CI 1.05-2.16; p=.026), Simpson ≥IV resections (HR: 2.41, 95%CI 1.52-3.84; p&amp;lt;.001), high-grade histology (HR: 3.70, 95%CI 2.50-5.47; p&amp;lt;.001) and male gender (HR: 1.46, 95%CI 1.01-2.11; p=.042) were independent risk factors for recurrence. Skull base location (HR: 1.92, 95%CI 1.17-3.17; p=.010 and HR: 2.02, 95%CI 1.04-3.95; p=.038) and high-grade histology (HR: 1.87, 95%CI 1.04-3.38; p=.038 and HR: 2.29, 95%CI 1.07-4.01; p=.034) but not subtotal resection (HR: 1.53, 95%CI .68-3.45; p=.303 and HR: 1.75, 95%CI .52-5.96; p=.369) remained independently correlated with recurrence after an event-free PFS of at least three (n=485) and five years (n=346), respectively. Similarly, postoperative tumor volume was related with recurrence in the entire cohort (p&amp;lt;.001) but not beyond a follow-up of ≥ three years (p&amp;gt;.05). In 147 patients with a follow-up of ≥ ten years, ten recurrences occurred, and no correlation was found with any of the analyzed variables. Conclusion Skull base tumor location and high-grade histology but not the extent of resection should be considered when planning follow-up duration and intervals following ≥5 years after meningioma surgery. Tumor relapses following more than ten years after surgery are very rare, and corresponding predictors are lacking.
P17.12.B HOXD13 gene plays a role as a putative master epigenetic regulator in glioma recurrence and progression
Authors: N S Morosini, T S Sabedot, S L Cazacu, A deCarvalho, H Noushmehr
Journal: Neuro-Oncology (2022)

Abstract Background Adult diffuse glioma is a heterogenous brain tumor group that has malignant potential and recurring properties. Glioma CpG island methylator phenotype (G-CIMP) associated with chromatin remodeling encompasses two different methylation degrees: G-CIMP-high and G-CIMP-low that have high levels of DNA methylation and loss of DNA methylation, respectively. G-CIMP-high confers a more favorable prognosis and better predictive values by altering transcriptional dynamics and inhibiting the gene expression. However, some IDH-mutant G-CIMP-high undergo a demethylation process progressing to G-CIMP-low leading to tumor recurrence and aggressiveness. Material and Methods We have performed Chromatin Immunoprecipitation Sequencing (ChIP-Seq) on DNA extracted from nine (9) fresh frozen primary tumor tissues belonging to G-CIMP-high group and four (4) belonging to G-CIMP-low group. We have processed the sequencing data by using FastQC (v.:0.11.5), bwa-mem (v.:0.7.15) and picard tool (v.:2.7.1). The ChIP-seq peaks and the differentially bound peaks were obtained using MACS2 (v.:2.1.1) and DiffBind (v.:3.4.11), respectively. We have integrated transcriptomic, epigenomic and genomic data to investigate the impact of H3K4me3 and H3K27ac in the epigenome of G-CIMP-low and high tumors. Results Initial results showed that the differentially bound H3K27ac and H3K4me3 peak gains and losses are located mainly in intronic and intergenic regions. The integration between epigenetic and transcriptomic data revealed that the promoter of the HOXD13 gene upregulated in GCIMP-low presents an active regulatory region and is enriched by H3K27ac and H3K4me3 sites. We were able to identify that GCIMP-low, in addition to presenting more downregulated genes than GCIMP-high, also has greater affinity to the H3K27ac peaks. In GCIMP-low, we identified 312 promoter regions significantly enriched by the epigenetic biomarker H3K27ac and 67 promoters with loss of affinity for H3K27ac, with the regions enriched by H3K27ac highly associated with the presence H3K4me3 marks. Functional genomic analysis targeting HOXD13 by using CRISPR in a representative glioma cell line shows that HOXD13 is critical for impairing the proliferative state that drives glioma progression.Conclusion: We mapped the enrichment of histone modifications in the TSS of differentially expressed genes in G-CIMP-high and G-CIMP-low identifying both the susceptibility of GIMP-low to interact with H3K27ac and the fact that the progression of GCIMP-high to G-CIMP-low can be explained by the association between H3K27ac gain and the inhibition of gene expression. Also, we predicted the HOXD13 gene as a putative master epigenetic regulator of the G-CIMP demethylation process and, consequently, of tumor recurrence and progression, over time.
P11.54.A Factors effecting early diagnosis in neurolymphomatosis
Authors: A Egert, P Karschnia, A Huttner, J M Baehring, L D Kaulen
Journal: Neuro-Oncology (2022)

Abstract Background Neurolymphomatosis is defined as infiltration of the peripheral nervous system by non-Hodgkin lymphoma (NHL). Given its rarity, correct diagnosis is often delayed. Here we assessed diagnostic work-up and factors affecting timely diagnosis at a tertiary referral center. Material and Methods The quality control database of the Section of Neuro-Oncology at Yale Cancer Center was searched for neurolymphomatosis cases seen between 2000 and 2021. Clinical, radiological and pathological findings were collected. Factors affecting the interval from symptom onset to diagnosis were investigated in univariate analysis using SPSS version 27. P-values &amp;lt;0.05 were considered statistically significant. Results We identified 22 cases of neurolymphomatosis (primary n=7, secondary n=15) with secondary disease diagnosed a median of 16 months (range: 4-144) after NHL. Patients presented with painful polyneuropathy (n=16), painless polyneuropathy (n=4), cranial neuropathy (n=3), and autonomic neuropathy (n=1). Diagnosis was nerve biopsy-based (n=11) or resulted from integration of imaging findings (n=11) with NHL history (n=5) or detection of NHL in the cerebrospinal fluid (n=6), respectively. Lesions localized to nerve roots (n=16), peripheral nerves (n=12), plexus (n=10), cranial (n=3) or autonomic (n=1) nerves. Histologically, most cases were classified as diffuse-large B-cell lymphoma (n=18). Median interval from symptom onset to diagnosis was 3 months (range: 1-12). Secondary neurolymphomatosis (p=0.02) and FDG-PET imaging (p&amp;lt;0.01) were associated with an earlier diagnosis. Conclusion Diagnosis of neurolymphomatosis requires a high degree of clinical suspicion with subsequent integration of clinical, radiological and pathological findings. FDG-PET, the imaging gold standard, and a known NHL history correlated with an earlier diagnosis.
P12.04.A Exosomes from glioma associated sphere forming cells induce a transition of invasive phenotype via transfer of EMP2 and CA9
Authors: S Kang, B Ryu, J Sa, H Kim, K Park, S Yu, D Hong, K Kim
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma multiforme (GBM) mostly occurs local recurrence at normal parenchyme adjacent tumor despite of conventional treatment. Glioma stem like cells (GSC) forming intratumoral heterogeneity within the GBM acquired the microenvironmental adaptation by inter-exosomal contents exchange between heterogenic cells. In addition, GSC has an invasive potential as like human GBM. Therefore, we investigate whether exosomal proteins of GSC affect the normal tissue invasion in GBM. Material and Methods Exosomes were isolated by Size-Exclusion method from conditioned media and validated by Electron microscope and Immunoblot assay. Exosomal proteomics were examined with Liquid Chromatography-Mass Spectrometry (LC/MS). To produce the fluorescent exosome, bi-cistron vectors were cloned with shRNA and CD63-GFP. To identify the effect of tranfected exosome, the isolated exosomes were treated to recipient cells and examined the invasion by 3D invasion assay and mouse intracranial model. Results Firstly, we dichotomized two groups following tumor invasion at matrigel assay and GSC derived orthotopic mouse model. CSC2 and X01 GSCs revealed highly invasive phenotype whereas 83NS and 528NS GSCs did not. Exosome was isolated in each group and identified by CD63 expression or electron microscopy. In proteomics analysis, hypoxia, extracellular matrix organization, GTPase cycle related proteins were enriched in highly invasive cell’s exosome. Among them, we focused the carbonic anhydrase IX (CA9) and the epithelial membrane protein 2 (EMP2) on its permissive role to glioblastoma invasion respectively. CA9 and EMP2 mRNA and protein levels were verified in GSCs and their exosomes and the high expression levels were detected in CSC2 and X01 compared to the low one in 83NS and 528NS GSCs. To evaluate the effects of CA9 and EMP2 on exosome mediated invasion potential, viral bi-cistron vectors was composed with the target gene knockdown and the CD63 fluorescence was used to detect intracellular exosome transfer. Interestingly, the decreased expression of phosphorylated FAK, a key invasive marker, was observed after Lentiviral mediated CA9- and EMP2-knockdown in highly invasive CSC2. To identify whether CA9 and EMP2 proteins are the intracellular effector protein responsible for exosome mediated glioma invasion, the donor exosomes (Exo-CSC2-sh-CA9 and Exo-CSC2-EMP2, after Lentiviral transfection to CSC2s) were isolated and treated to the non invasive 528NS cells as recipient cells. In 3D invasion assay, Exo-CSC2-shCA9 or Exo-CSC2-shEMP2 mediated tumor invasion was significantly decreased at 528NS GSCs compared to Exo-CSC2-shEV. These features were found at mouse intracranial model as well. Conclusion Together with these, we conclude that exosome derived from GSCs induces a transition of invasive phenotype via transfer of EMP2 and CA9 proteins.
P11.22.A Prognostic and predictive relevance of immunohistochemically determined p53 mutation in glioblastoma
Authors: J Kempter, J Gempt, B Wiestler, S E Combs, J Schlegel, F Liesche-Starnecker, F Schmidt-Graf
Journal: Neuro-Oncology (2022)

Abstract Background It can be expected that molecular biomarkers will increasingly affect clinical decisions and lead to the development of more personalized therapies in glioblastoma (GBM) in the future. In several other tumor entities TP53 gene mutation or p53 immunoreactivity (IR) serve as a prognostic marker, significantly affecting overall survival (OS) and progression-free survival (PFS). Such an association has not yet sufficiently been demonstrated in GBM. However, there are known prognostic markers in GBM, notably MGMT promotor methylation (mMGMT) which also serves as an important predictive marker leading to a better response to temozolomide chemotherapy. Our aim was to evaluate retrospectively if p53 mutation determined via immunohistochemistry (IHC) could act as a prognostic or predictive marker in GBM. Material and Methods Tumor samples of 195 treatment-naïve patients with IDHwt GBM that had been stained with the p53 antibody DO-7 were subdivided into 2 different groups by p53 IHC. Samples were considered as p53mut when strong p53 IR was detected in ≥10% of all tumor cells and as p53wt when in &amp;lt;10%. Treatment, further molecular and survival data were gathered retrospectively for all patients. Statistical analyses were performed with SPSS. Results The frequency of p53mut was 36.4% (71/195). p53mut tumors showed a significantly higher IR with Ki-67 proliferation marker (p=0.005) and p53wt seemed to be associated with multifocal primary tumor localization, though not statistically significant (p=0.107). There was no significant difference between p53wt and p53mut regarding gender, age, extent of resection, adjuvant therapy, occurrence of seizures, mMGMT or ATRX loss. The p53 status was not associated with OS or PFS. Factors that univariately led to significantly longer OS and PFS were younger age, unilateral or unifocal primary tumor localization, gross-total resection, higher Karnofsky Performance Status (KPS), mMGMT and adjuvant treatment via Stupp regimen instead of radiotherapy alone, the latter being significantly better than best supportive care. In multivariate survival analyses only age &amp;lt;65 years, the Stupp regimen more than radiotherapy alone and KPS ≥80% significantly prolonged both OS and PFS. Unifocal primary tumor localization led to longer OS and mMGMT led to longer PFS independently. The p53 status did not significantly affect the response to different adjuvant therapy regimens neither concerning OS nor PFS. Conclusion Based on our study, p53 IR has no prognostic or predictive significance in IDHwt GBM. There have been previous studies with similar and others with contradicting results. Remarkable is the discordance of the used IR thresholds between different studies. Further studies should aim to revalidate the staining threshold and improve the concordance between TP53 gene sequencing and p53 IHC in IDHwt GBM.
P05.03.B Application of rapid cytology in intraoperative diagnosis of primary central nervous system lymphoma
Authors: H Liwen, W Xingfu, Z Limei
Journal: Neuro-Oncology (2022)

Abstract Background To assesment the value of rapid cytological diagnosis in primary central nervous system lymphoma (PCNSL) surgery. Material and Methods A total of 213 PCNSL specimens from the First Affiliated Hospital of Fujian Medical University between 2012 to 2022 were included, 1-2mm3 was taken from the tissues diagnosed for intraoperative pathology and made into cell smears, rapid cytological diagnosis was performed after 95% ethanol fixation and H&amp;E staining, most of the remaining tissues were diagnosed by frozen section. With the results of paraffin section pathological diagnosis as the control standard, compared the accuracy of rapid cytology and frozen tissue section and their combined diagnosis. Results Cytological smears can reveal microscopic structures within the cells under a microscope, furthermore, it can avoid the formation of artifacts or deformation of cells when frozen due to excessive water in brain tissue. Compared with paraffin section pathological diagnosis, the diagnostic accuracy of rapid cytology was 151cases (70.89%) , that of frozen tissue section was 175 cases (82.16%) , and that of the combination of the two methods was 187 cases (87.79%) . There were 26 cases (12.21%) in which neither method could give a definite conclusion intraoperatively and only depended on the results of paraffin tissue sections. Conclusion Rapid cytology alone is less accurate in diagnosing PCNSL than frozen sections alone. However, the combination of the two diagnosis can improve the accuracy of intraoperative diagnosis of PCNSL and correct some errors that may occur when only relying on frozen section diagnosis. It is especially suitable for stereotactic biopsy surgery or cases with very little tissue, as well as primary medical units without frozen section machine and other equipment.
P11.75.B Survival benefit of radiotherapy and surgery in patients with lung cancer brain metastases with poor prognosis factors
Authors: L Liang, Z Wang, H Duan, J Lu, X Jiang, H Hu, C Li, C Yu, S Zhong, R Cui, X Guo, Z He, L Chen, Y Mou
Journal: Neuro-Oncology (2022)

Abstract Background Radiotherapy and surgery are the standard treatments for lung cancer brain metastases (BMs). However, limitted studies focused on the treatments for patients with lung cancer BMs with poor prognosis factors. The purpose of this study was to investigate the effects of radiotherapy and surgery in patients with lung cancer BMs with poor prognosis factors, providing reference for clinical strategies. Material and Methods We analyzed retrospectively 714 patients with lung cancer BMs. A 1:1 propensity score matching (PSM) was performed to balance potential confounders. Analyses of overall survival (OS) and risk factors for OS were assessed by log-rank test and Cox proportional hazard model. Results Age ≥65 years, Karnofsky Performance Scale (KPS) score ≤70, anaplastic large-cell lymphoma kinase (ALK)/epidermal growth factor receptor (EGFR) wild type, extracranial metastases, non-surgery and non-radiotherapy led to poor prognosis. Patients were stratified according to these factors. Radiotherapy and surgery showed no survival benefit in patients with aged ≥65 years or pretreatment KPS score ≤70 before and after PSM. Before PSM, whole brain radiotherapy (WBRT) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or extracranial metastases. WBRT also predicted good prognosis in patients with non-surgery. Stereotactic radiosurgery (SRS) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or non-surgery. WBRT plus SRS improved the OS and predicted good prognosis in patients with extracranial metastases or non-surgery. WBRT plus SRS also predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS and predicted good prognosis in patients with non-radiotherapy. After PSM, SRS improved the OS and predicted good prognosis in patients with non-surgery. WBRT plus SRS improved the OS and predicted good prognosis in patients with non-surgery or extracranial metastases. WBRT plus SRS also predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS of patients with non-radiotherapy. We defined that the treatment would provide significant survival benefit if it both prolonged the OS and predicted good prognosis. Meanwhile, the results after PSM were more convincing than the results before PSM. Conclusion Radiotherapy has significant survival benefit in patients with lung cancer BMs with poor prognosis factors, including patients with ALK/EGFR wild type or extracranial metastases or non-surgery. Surgery only has significant survival benefit in patients with non-radiotherapy.